This project delineates biochemical and pharmacological properties of sigma-1 receptors (S-1R). S-1R are one-transmembrane proteins at the endoplasmic reticulum (ER) that bind neurosteroids, dextrobenzomorphans, and certain psychostimulants such as cocaine. The brain is highly enriched in lipids. However, the molecular biological roles of lipids in the brain have been largely unexplored. Although, in 1990s, several studies have demonstrated the roles of lipids in a variety of neuronal functions and certain neurological diseases, the involvement of lipids in drug dependence, if any, is almost totally unknown. Sigma-1 receptors possess a putative sterol-binding pocket and are predominantly expressed on the endoplasmic reticulum (ER) where most lipids and their precursors are synthesized. Sigma-1 receptors are involved in drug-seeking behaviors and in psychostimulant-induced behavioral sensitization. Recent studies demonstrated that sigma-1 receptors target the lipid-storing subcompartments of the ER and are colocalized with cholesterol and neutral lipids. Sigma-1 receptors form detergent-insoluble lipid microdomains (lipid rafts) on the ER subcompartments and can translocate on the ER when stimulated. Upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts including tropic factor receptors and tyrosine kinases. Specifically, we found that sigma-1 receptors modulate MAP kinase activation induced by tropic factors, neuritegenesis and oligodendrocyte differentiation-all related to lipid raft reconstitution. Sigma-1 receptors may thus play a role in psychostimulant-induced long-lasting morphological changes in the brain via the capacity of sigma-1 receptors in regulating ER lipid transport and the resultant plasma membrane lipid raft reconstitution.